Dietary phytoestrogen intake and ovarian cancer risk: a prospective study in the prostate, lung, colorectal and ovarian (PLCO) cohort.

Estrogen plays a crucial role in ovarian tumorigenesis. Phytoestrogens (PEs) are a type of daily dietary nutrient for humans and possess a mild estrogenic characteristic. This study aimed to assess the correlation of the consumption of dietary PEs with ovarian cancer risk using data in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Participants were enrolled in PLCO from 1993 to 2001. Hazard ratios (HR) and 95% confidence intervals (CI) were utilized to determine the association between the intake of PEs and ovarian cancer occurrence, which were calculated by the Cox proportional hazards regression analysis. In total, 24 875 participants were identified upon completion of the initial dietary questionnaire (DQX). Furthermore, the analysis also included a total of 45 472 women who filled out the diet history questionnaire (DHQ). Overall, after adjustment for confounders, the dietary intake of total PEs was significantly associated with the risk of ovarian cancer in the DHQ group (HRQ4vsQ1 = 0.69, 95% CI: 0.50-0.95; P for trend = 0.066). Especially, individuals who consumed the highest quartile of isoflavones were found to have a decreased risk of ovarian cancer in the DHQ group (HRQ4vsQ1 = 0.68, 95% CI: 0.50-0.94; P for trend = 0.032). However, no such significant associations were observed for the DQX group. In summary, this study suggests that increased dietary intake of total PEs especially isoflavones was linked with a lower risk for developing ovarian cancer. More research is necessary to validate the findings and explore the potential mechanisms.

Emerging role of mesenchymal stromal cells in gynecologic cancer therapy.

Mesenchymal stromal cells (MSCs) show considerable promise in regenerative medicine with superior anti-fibrotic, immunomodulatory, and angiogenic functions. More recently, discovered with the tumor tropism, MSCs have been exploited as the basis of targeted cancer therapy. In this scenario, MSCs can directly home to tumor tissues and play anti-tumor properties. In addition, MSCs, MSC-derived exosomes and MSC-derived membranes are often developed as carriers for precisely delivering cytotoxic agents to cancer sites, including chemotherapeutic drugs, therapeutic genes, or oncolytic viruses. However, it has revealed the tumorigenic risk of MSCs as an important component within the tumor microenvironment, hampering the translation of MSC-based cancer therapies into clinical settings. Therefore, in this review, we introduce the specific tumor-tropic ability of MSCs and underlying mechanisms. We also summarize the current application of MSC-based therapeutic approaches in treating gynecologic cancers, mainly including cervical, ovarian, and endometrial cancers. Moreover, we discuss the main challenges that the current MSC-based cancer therapies are facing.

The role of DYNLT3 in breast cancer proliferation, migration, and invasion via epithelial-to-mesenchymal transition.

PURPOSE: DYNLT3 is identified as an age-related gene. Nevertheless, the specific mechanism of its carcinogenesis in breast tumor has not been clarified. This research aims to elucidate the role and the underlying molecular pathways of DYNLT3 on breast cancer tumorigenesis. METHODS: The differential expression of DYNLT3 among breast cancer, breast fibroids, and normal tissues, as well as in various breast cancer cell lines were detected by immunohistochemical staining, real-time quantitative reverse transcription-PCR and Western blotting, respectively. Additionally, the role of DYNLT3 on cell viability and proliferation were observed through cell counting kit-8, bromodeoxyuridine, and colony formation experiments. Migratory and invasive abilities was envaulted by wound healing and Transwell methods. Apoptotic cells rate was examined by flow cytometry. Furthermore, nude mice xenograft models were established to confirm the role of DYNLT3 in tumor formation in vivo. RESULTS: DYNLT3 expression was highly rising in both breast cancer tissues and cells. DYNLT3 knockdown obviously suppressed cell growth, migration and invasion, and induced cell apoptosis in MDA-MB-231 and MCF-7 breast cancer cells. The overexpression of DYNLT3 exerted the opposite effect in MDA-MB-231 cells. Moreover, DYNLT3 knockdown inhibited tumor formation in vivo. Mechanistically, an elevation of N-cadherin and vimentin levels and a decline of E-cadherin were observed when DYNLT3 was upregulated, which was reversed when DYNLT3 knockdown was performed. CONCLUSION: DYNLT3 may function as a tumor-promotor of age-associated breast cancer, which is expected to provide experimental basis for new treatment options.

Cell Membranes from Tumor-Tropic MSCs Screened by a Microfluidic Chip for Drug Nanoparticles Encapsulation and Cancer Targeted Therapy.

Nanoparticles (NPs)-based drug carriers are effective in reducing systemic toxicity and drug resistance for chemotherapy, and an emerging trend focuses on integrating cell membranes with nanomedicines for tumor targeting. Mesenchymal stem cells (MSCs) are promising candidates due to their unique tropism toward cancer cells, yet the tumor-tropic abilities can differ for MSCs sourced from different tissues. Here, a multichannel microfluidic chip to screen different sourced MSCs with the greatest tropism toward cervical cancer cells is developed. Based on this, the cell membranes from the chorionic plate-derived MSC are isolated and membrane-camouflaged platinum prodrug composite NPs for cervical cancer treatment are prepared. Results demonstrate that the composite NPs can effectively target tumor sites and have a therapeutic effect both in vitro and in vivo. It is believed that the present microfluidic platform is a powerful tool for cell screening and tumor-on-a-chip studies, and the derived nanodelivery system represents the great value of cell membrane-camouflaged nanomedicine for targeted cancer therapy.

DHODH Inhibition Exerts Synergistic Therapeutic Effect with Cisplatin to Induce Ferroptosis in Cervical Cancer through Regulating mTOR Pathway.

Ferroptosis exhibits a potent antitumor effect and dihydroorotate dehydrogenase (DHODH) has recently been identified as a novel ferroptosis defender. However, the role of DHODH inhibition in cervical cancer cells is unclear, particularly in synergy with cisplatin via ferroptosis. Herein, shRNA and brequinar were used to knock down DHODH and directly inhibit DHODH, respectively. Immunohistochemistry and Western blotting assays were performed to measure the expression of proteins. CCK-8 and colony formation assays were employed to assess the cell viability and proliferation. Ferroptosis was monitored through flow cytometry, the malondialdehyde assay kit and JC-1 staining analyses. The nude mouse xenograft model was generated to examine the effect of combination of DHODH inhibition and cisplatin on tumor growth in vivo. The expression of DHODH was increased in cervical cancer tissues. DHODH inhibition inhibited the proliferation and promoted the ferroptosis in cervical cancer cells. A combination of DHODH inhibition and cisplatin synergistically induced both in vitro and in vivo ferroptosis and downregulated the ferroptosis defender mTOR pathway. Therefore, the combination of DHODH inhibition and cisplatin exhibits synergistic effects on ferroptosis induction via inhibiting the mTOR pathway could provide a promising way for cervical cancer therapy.

Differences in chemotaxis of human mesenchymal stem cells and cervical cancer cells.

In the last decade, there has been a rapid expansion in tumor targeted therapy using mesenchymal stem cells (MSCs) based on their unique tropism towards cancer cells. Despite similarities in morphology, immunophenotype, and differential potent in vitro, MSCs originated from different tissues do not necessarily have equivalent biological behaviors. It is important to screen the most chemotactic MSCs to cancer cells. In this study, different MSCs were isolated from various human tissues including adipose, umbilical cord, amniotic membrane, and chorion. The chemotaxis of human MSCs to cervical cancer cells was measured by CCK-8, ELISA and Transwell invasion assays. Western blotting was performed to explore the underlying mechanisms. MSCs derived from distinct sources can be differently recruited to cervical cancer cells, among which chorion-derived MSC (CD-MSC) possessed the strongest tropic capacity. CXCL12 was found to be highly secreted by cervical cancer cells, in parallel with the expression of CXCR4 in all MSCs. CD-MSC displayed the highest level of CXCR4. These results indicated that CXCL12/CXCR4 pathway contributed to the different chemotaxis to cervical cancer cells of each MSCs. This study proposed that CD-MSC with the highest CXCR4 expression is a promising therapeutic vehicle for targeted therapy in cervical cancer.

Erratum: Effects of Galectin-1 on Biological Behavior in Cervical Cancer: Erratum.

[This corrects the article DOI: 10.7150/jca.38538.].

MAT2A facilitates PDCD6 methylation and promotes cell growth under glucose deprivation in cervical cancer.

The underlying mechanisms of methionine adenosyltransferase 2 A (MAT2A)-mediated cervical cancer progression under nutrient stress are largely elusive. Therefore, our study aims to investigate molecular mechanism by which MAT2A-indcued cervical oncogenesis. The interaction between MAT2A and programmed cell death protein 6 (PDCD6) in cervical cancer cell lines was detected by immunoprecipitation, immunoblotting and mass spectrometric analysis. A panel of inhibitors that are linked to stress responsive kinases were utilized to detect related pathways by immunoblotting. Cell proliferation and apoptosis were investigated by CCK-8 and flow cytometry. Apoptosis related protein level of Bcl-2, Bax and Caspase-3 was also analyzed in cells with PDCD6 K90 methylation mutation. The association between MAT2A and PDCD6 was detected by immunohistochemistry and clinicopathological characteristics were further analyzed. We found that the interaction between MAT2A and PDCD6 is mediated by AMPK activation and facilitates PDCD6 K90 methylation and further promotes protein stability of PDCD6. Physiologically, expression of PDCD6 K90R leads to increased apoptosis and thus suppresses growth of cervical cancer cells under glucose deprivation. Furthermore, the clinical analysis indicates that the MAT2A protein level is positively associated with the PDCD6 level, and the high level of PDCD6 significantly correlates with poor prognosis and advanced stages of cervical cancer patients. We conclude that MAT2A facilitates PDCD6 methylation to promote cervical cancer growth under glucose deprivation, suggesting the regulatory role of MAT2A in cellular response to nutrient stress and cervical cancer progression.

Insight into the role of multiple signaling pathways in regulating cancer stem cells of gynecologic cancers.

Mounting evidence has demonstrated that a myriad of developmental signaling pathways, such as the Wnt, Notch, Hedgehog and Hippo, are frequently deregulated and play a critical role in regulating cancer stem cell (CSC) activity in human cancers, including gynecologic malignancies. In this review article, we describe an overview of various signaling pathways in human cancers. We further discuss the developmental roles how these pathways regulate CSCs from experimental evidences in gynecologic cancers. Moreover, we mention several compounds targeting CSCs in gynecologic cancers to enhance the treatment outcomes. Therefore, these signaling pathways might be the potential targets for developing targeted therapy in gynecologic cancers.

Insights Into the Biological Role of NEDD4L E3 Ubiquitin Ligase in Human Cancers.

Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) is an E3 ubiquitin ligase that has been reported to participate in multiple cellular procedures by regulating of substrate ubiquitination and subsequent protein degradation. A great amount of evidence has demonstrated that NEDD4L mainly functions as a tumor suppressor in most cancer types, while it also acts as an oncogene in a few cancers. In this review, we summarize the potential role of NEDD4L in carcinogenesis and the related underlying molecular mechanism to improve our understanding of its functions in the tumorigenesis of human malignancies. Developing clinical drugs targeting NEDD4L could be a potential therapeutic strategy for cancer therapy in the future.

METTL3 increases cisplatin chemosensitivity of cervical cancer cells via downregulation of the activity of RAGE.

Cervical cancer is the most common gynecologic malignancy worldwide. Methyltransferase-like 3 (METTL3) is involved in tumorigenesis; however, it is unclear whether METTL3 plays a potential role in regulating cisplatin (DDP) resistance. Therefore, the role of METTL3 in the regulation of cisplatin sensitivity in cervical cancer cells was determined. Our immunohistochemistry (IHC) data showed that METTL3 was highly expressed in para-cancerous compared with cervical cancer tissues. Furthermore, METTL3 overexpression inhibited viability and increased cisplatin sensitivity of cervical cancer cells in vitro. Overexpression of METTL3 inhibited tumor growth in vivo. IHC results showed that the receptor for advanced glycation and products (RAGE) had higher expression levels in cervical cancer tissues. RAGE downregulation increased cell sensitivity to cisplatin treatment. Moreover, the combination of FPS-ZM1 with cisplatin was more effective in inhibiting cell viability as compared with FPS-ZM1 or cisplatin only. Additionally, METTL3 reduced RAGE expression in cervical cancer cells. Overexpression of METTL3 downregulated RAGE expression and caused more sensitivity to cisplatin treatment in the SiHa-DDP cell line. METTL3 inhibited cell viability and increased apoptosis as well as enhanced the sensitivity of cisplatin via downregulating RAGE expression in cervical cancer cells.

Aquaporin-8 is a novel marker for progression of human cervical cancer cells.

BACKGROUND: Role of aquaporin-8 (AQP8) in cervical cancer has not been fully elucidated. OBJECTIVE: We aim to explore the impacts of AQP8 on viability, apoptosis and metastasis in cervical cancer cells. METHODS: AQP8 protein expression in cervical carcinoma specimens and cell lines was detected by IHC and western blot analysis. Lentivirus-mediated transfection was used to upregulate and knockdown AQP8 in cells. Cell viability and apoptosis were assessed by CCK-8 and flow cytometry assays, respectively. Transwell experiments were conducted to investigate cell invasive and migratory capabilities. EMT-related markers were detected by western blot analysis. RESULTS: A strong positive of AQP8 protein expression was observed in cervical cancer tissues. Western blot analysis confirmed overexpression and knockdown of AQP8 in SiHa cells. AQP8-overexpressed SiHa cells displayed an enhanced viability, reduced apoptotic rate, increased invasive and migratory abilities. Knockdown of AQP8 inhibited the viability, promoted the apoptosis, and suppressed invasion and migration. Furthermore, AQP8 overexpression significantly upregulated vimentin and N-cadherin, and downregulated E-cadherin, which were reversed by AQP8 knockdown. CONCLUSIONS: AQP8 increases viability, inhibits apoptosis, and facilitates metastasis in SiHa cells. This may be associated with EMT-related markers regulated by AQP8. AQP8 could serve as a potential marker for cervical cancer progression.

Association between vitamin D and uterine fibroids: a study protocol of an open-label, randomised controlled trial.

INTRODUCTION: Uterine fibroids are the most common pelvic benign tumour with no satisfactory long-term medical treatment. Recent studies have demonstrated that vitamin D significantly inhibited the growth of fibroids in vitro, vivo and a small-sample clinical trial. Therefore, the aim of this randomised clinical trial (RCT) is to evaluate whether supplementation with vitamin D could reduce the risk and inhibit the growth of uterine fibroids in reproductive stage women. METHODS AND ANALYSIS: The open-label, RCT comprises two parts, including parts I and II. In part I, 2230 vitamin D deficiency or vitamin D insufficiency patients without uterine fibroids will be randomly assigned to two groups: intervention group (according to the level of serum 25-hydroxyvitamin D3, receive 1600 or 800 IU/day of vitamin D3 for 2 years) and control group (followed up at the same time points). By using gynaecological ultrasound examinations, the incidence of uterine fibroids will be employed to measure the outcome in different groups. In part II, 360 uterine fibroids patients with vitamin D deficiency or vitamin D insufficiency will be randomly assigned to intervention group or control group. According to the level of serum 25-hydroxyvitamin D3, 180 patients will receive 1600 or 800 IU/day of vitamin D3 for 2 years. Control group will receive regular follow-up. The outcome measure will be conducted using gynaecological ultrasound examinations to detect the growth of uterine fibroids in each group. ETHICS AND DISSEMINATION: This study has been approved by the institutional review board of the Second Affiliated Hospital of Wenzhou Medical University (No. LCKY2018-35). TRIAL REGISTRATION NUMBERS: NCT03586947 and NCT03584529.

Quercetin Inhibits Adenomyosis by Attenuating Cell Proliferation, Migration and Invasion of Ectopic Endometrial Stromal Cells.

PURPOSE: To evaluate the effects of quercetin on proliferation, invasion and migration of endometrial stromal cells (ESCs) from adenomyosis patients. METHODS: Primary ectopic ESCs (EESCs) and eutopic ESCs (EuESCs) were obtained and purified from patients undergoing total hysterectomy for adenomyosis and identified by immunocytochemistry staining. The cytotoxicity and inhibition rate were determined by CCK-8 assay to obtain the IC50 value. Cell proliferative, migratory, and invasive abilities were detected by BrdU, wound scratch, transwell assays, respectively. Western blot analysis was employed to explore the effects of quercetin on the expression of MMP-2, MMP-9, Ezrin and Fascin proteins in cells. RESULTS: Both EESCs and EuESCs were characterized with strongly positive staining for vimentin and almost negative for cytokeratin. Quercetin inhibited the viability of EESCs and EuESCs in a dose- and time-dependent manner, with an IC50 = 33.00 µM for EuESCs and IC50 = 74.88 µM for EESCs at 72 h. Thus, the final concentrations and action time of quercetin in EuESCs (0, 20, 40, and 80 µM for 72 h) and EESCs (0, 40, 80, and 160 µM for 72 h) were selected. BrdU assay showed that quercetin dose-dependently suppressed the proliferation of EESCs and EuESCs, while the inhibition rate in EESCs was higher. Similarly, administration of quercetin in EESCs and EuESCs significantly decreased the motility and invasiveness in a dose-dependent fashion, with stronger inhibitory effects on EESCs. Finally, Western blot analysis demonstrated that invasion- and migration-related proteins (MMP-2, MMP-9, Erzin, and Fascin) were significantly downregulated with the quercetin concentration increasing. Moreover, the decreased level of these proteins in EESCs under quercetin exposure was greater than that in EuESCs. CONCLUSION: Quercetin can inhibit the proliferation of EESCs in adenomyosis and reduce their mobility and invasiveness. These inhibitory effects may be related to the downregulation of MMP-2, MMP-9, Fascin, and Erzin proteins.

Atorvastatin suppresses the progression of cervical cancer via regulation of autophagy.

Atorvastatin (ATO), one of the most common cholesterol reduction agents, exhibits anti-neoplastic effects in several human cancers. However, the antitumor effects of ATO on cervical cancer have not been extensively reported. Recently, autophagy inhibitors are reported to enhance the efficacy of chemotherapeutics. Here, we showed that ATO reduced cell viability and promoted apoptosis of cervical cancer cells by inducing caspase-3 and PARP activation and upregulating Bim. Treatment of ATO also suppressed tumor growth in vivo. In addition, co-culture with GGPP almost completely reversed the morphological change and apoptosis induced by ATO in cervical cancer cells. Furthermore, ATO induced cellular autophagy in cervical cancer cells, which was confirmed by an increase of LC3-I into LC3-II conversion, downregulation of p62 expression, regulation of AMPK and Akt/mTOR pathways. Moreover, pharmacologic inhibition of autophagy using either Baf-A1 or 3-MA significantly enhanced ATO-mediated apoptosis on cervical cancer cells. In conclusion, combination of ATO with autophagy inhibitors could emerge as a new therapeutic strategy for cervical cancer treatment.

The Prognostic Value of the Chromobox Family in Human Ovarian Cancer.

Ovarian cancer is one of the most lethal gynecologic tumors in women and has a poor prognosis. The purpose of our study was to identify new prognostic markers in ovarian cancer. We examined the prognostic roles of mRNA expression of the chromobox (CBX) family in patients with ovarian cancer utilizing the Kaplan-Meier plotter database. The prognostic values and expression levels of CBX members associated with prognosis were further evaluated using KM plotter in diverse subgroups and immunohistochemistry (IHC) analysis in ovarian carcinoma. The results revealed that elevated CBX1-3 mRNA expression may predict poor overall survival (OS) and progression-free survival (PFS) outcomes in patients with ovarian cancer. Notably, in women with ovarian cancer, increased CBX1 mRNA expression was linked to a short OS in all stages and in the grade II and grade III subgroups. Additionally, CBX2 and CBX3 were strongly related to short OS in stage III+IV patients, and a link between high CBX3 mRNA expression and unfavorable OS in grade II patients was observed. High expression levels of CBX1 and CBX3 were significantly associated with chemotherapy resistance in ovarian cancer patients. IHC staining showed that the CBX1-3 proteins were upregulated in serous ovarian carcinoma tissues compared with normal ovarian tissues. Therefore, our results indicated that CBX1-3 could be attractive biomarkers for predicting poor prognosis of ovarian cancer.

Evolving roles of lysyl oxidase family in tumorigenesis and cancer therapy.

The lysyl oxidase (LOX) family is comprised of LOX and four LOX-like proteins (LOXL1, LOXL2, LOXL3, and LOXL4), and mainly functions in the remodeling of extracellular matrix (ECM) and the cross-linking of collagen and elastic fibers. Recently, a growing body of research has demonstrated that LOX family is critically involved in the regulation of cancer cell proliferation, migration, invasion and metastasis. In this review, we discuss the roles of LOX family members in the development and progression of different types of human cancers. Furthermore, we also describe the potential inhibitors of LOX family proteins and highlight that LOX family might be an important therapeutic target for cancer therapy.

Aquaporin 1 affects pregnancy outcome and regulates aquaporin 8 and 9 expressions in the placenta.

To explore the effects of aquaporin (AQP) 1 on pregnancy outcome and the association between expression of AQP1 and other AQPs in the placenta and foetal membranes, the rate of copulatory plugs and pregnancy, amniotic fluid (AF) volume, osmolality and composition were determined in AQP1-knockout (AQP1-/-) mice at different gestational days (GD). The expression and location of AQP1 and other AQPs in the placenta and foetal membranes of AQP1-/- mice, AQP1-siRNA transfected WISH cells and oligohydramnios patients were also detected. Compared to control mice, AQP1-/- mice exhibited reduced copulation plug and successful pregnancy rates, but these effects were accompanied by a larger AF volume and lower AF osmolality at late gestation. AQP9 expression was significantly decreased in the placenta and foetal membranes of AQP1-/- mice, while AQP8 level was elevated in the foetal membranes of AQP1-/- mice. Moreover, AQP9 expression was suppressed in WISH cells after AQP1 downregulation. Furthermore, AQP9 expression was associated with AQP1 level in the placenta and foetal membranes in oligohydramnios. AQP1 may play a critical role in regulating pregnancy outcome and maternal-foetal fluid homeostasis. Changes in AQP1 expression may lead to compensatory alterations in AQP8 and AQP9 expression in the placenta.

The diverse roles of SPOP in prostate cancer and kidney cancer.

Multiple studies have confirmed that speckle-type pox virus and zinc finger (POZ) protein (SPOP) functions as a substrate adaptor of cullin 3-based E3 ligase and has a crucial role in various cellular processes via specific targeting of proteins for ubiquitination and subsequent proteasomal degradation. Dysregulation of SPOP-mediated proteolysis might be involved in the development and progression of human prostate and kidney cancers. In prostate cancer, SPOP seems to function as a tumour suppressor by targeting several proteins, including androgen receptor (AR), steroid receptor coactivator 3 (SRC3) and BRD4, for degradation, whereas it might function as an oncoprotein in kidney cancer, for example, by targeting phosphatase and tensin homologue (PTEN) for proteasomal degradation. In addition, nuclear SPOP targets AR for degradation and has a role as a tumour suppressor in prostate cancer; however, in kidney cancer, SPOP largely accumulates in the cytoplasm and fails to promote degradation of AR located in the nucleus, resulting in activation of AR-driven pathways and cancer progression. Owing to the context-dependent function of SPOP in human malignancies, further assessment of the molecular mechanisms involving SPOP in prostate and kidney cancers is needed to improve our understanding of its role in the development of these cancer types. Treatments that target SPOP might become therapeutic strategies in these malignancies in the future.

Downregulation of RAGE Inhibits Cell Proliferation and Induces Apoptosis via Regulation of PI3K/AKT Pathway in Cervical Squamous Cell Carcinoma.

AIM: The receptor for advanced glycation endproducts (RAGE) expression has been reported to be implicated with cancer development. In this study, the role of RAGE in the regulation of cervical squamous cancer cell proliferation, apoptosis and the mechanism of RAGE involved in the biological behaviors were explored. METHODS: The RAGE expression was overexpressed or downregulated by lentivirus transfection. The effect of RAGE expression on cell proliferation was explored by CCK-8, MTT, and BrdU assay, and the effect of RAGE on tumor development was confirmed by the xenograft mouse model along with the immunohistochemistry stain of proliferating cell nuclear antigen (PCNA). Apoptosis was investigated by flow cytometry and TUNEL assay. Western blotting was performed to investigate the expression of possible proteins, including Bax, Bcl-2, PI3K, p-PI3K, AKT, and p-AKT. RESULTS: Overexpression of RAGE promoted proliferation of cervical squamous cancer cell and increased PCNA expression. In the meantime, RAGE overexpression inhibited cell apoptosis along with a decrease of Bax/Bcl-2 ratio, and induction of PI3K/AKT activation. The in vivo results showed that overexpression of RAGE enhanced tumor growth. Conversely, knockdown of RAGE exhibited opposed effects on cervical cancer cells and xenograft mouse model. Furthermore, RAGE inhibitor FPS-ZM1 effectively inhibited SiHa cell viability and PCNA expression, and increased cell apoptosis and Bax/Bcl-2 ratio. Moreover, PI3K inhibitor LY294002 effectively inhibited activation of PI3K and AKT, and further repressed RAGE overexpression-induced cell proliferation and apoptosis inhibition. CONCLUSION: RAGE promotes the growth ability of cervical squamous cell carcinoma by inducing PCNA expression and inhibiting cell apoptosis via inactivation of the PI3K/AKT pathway.